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Genetics (Pediatrics) - Coggle Diagram
Genetics (Pediatrics)
BASIC PRINCIPLES OF HUMAN GENETICS
Term
Homozygous
individuals with identical alleles for a given locus
Heterozygous
individuals with different alleles for a particular locus
Dominant trait
f a gene in a pair specifies the phenotype instead of the other gene
Recessive
traits or disease that manifest only when both copies of genes are the same
Chromosome
pair comes from the mother and the other from the father
46 pairs of chromosomes
Germs cells
22 pairs of autosomes
pair of sex
XX in females
XY in males
Centromere
1 or 2 arms projecting from each chromosome
Short arm
Long arm
Genetic Counseling
first and most important step in genetic counseling is collecting relevant data. A family tree or pedigree is drawn using internationally accepted symbols.
MENDELIAN GENETICS
X-LINKED DOMINANT INHERITANCE
Characteristics
Similar to autosomal dominant disease
Affected males with normal mates have no affected sons and no normal daughters
female carriers have 50% risk of inheriting the phenotype
Affected females are about twice as common as affected males
Examples
Focal Dermal hypoplasia, Vitamin D resistant rickets, Rett syndrome,incontinentia pigmenti (lethal in males)
X-LINKED RECESSIVE INHERITANCE
Examples
Color blindness, Hemophilia A and B and Duchenne muscular dystrophy
a pattern of X inactivation (normal physiological process in which 1 X chromosome is largely inactivated in somatic cells in normal females)
Glucose-6-phosphate Dehydrogenase Deficiency (G6PD)
Deficiency – accumulation of free radicals inside the cell, leading to membrane damage
Manifestations
Hemoglobiuria, jaundice and anemia
Management
Discontinue causative agent
Supportive blood transfusion – for severe hemolysis
Hemophilia
deficiency of clotting factors VIII (Hemo A) and IX (Hemo B)
Manifestations
Hemarthrosis or spontaneous bleeding into joints, commonly in the ankles.
Easy bruisability and intramuscular hematoma
Management
Factor replacement
Duchenne Muscular Dystrophy
mutation in dystropin gene
Usual onset of symptoms: between 3-5yo
Muscle weakness – frequent falls, fatigue and awkward gait
No known cure
AUTOSOMAL RECESSIVE INHERITANCE
Maple Syrup Urine Disease (MSUD)
Deficiency of branched-chain alpha-keto acid dehydrogenase
Sign
poor suck, lethargy, hypotonia or hypertonia, vomiting, fussiness and a high-pitched cry.
Treatment
Dietary restriction and titration
peritoneal dialysis, hemodialysis,hemofiltration
Provide high-energy fluids or special formula
Liver transplantation
Galactosemia
Elevation of blood galactose levels due to deficiency of any of 3 enzymes of galactose catabolic pathway
Galactokinase
GK, chromosome 15 and 17
GALE
Uridine diphosphate-galactose-4-epimerase (chromosome 1)
GALT
Galactose-1-phosphate uridyl transferase (chromosome 9)
Manifestations
Jaundice, heatomegaly, vomiting, hypoglycemia, convulsions, lethargy, irritability, feeding difficulties and poor weight gain, Cataracts within days or weeks
Treatment
Dietary restriction of galactose and lactose
Use of soy-based formula
Congenital Adrenal Hyperplasia
Deficiency in any of the enzymes required for the synthesis of
aldosterone and cortisol
Manifestations
Females
ambiguous genitalia, clitoral enlargement, normal ovaries and amenorrhea at puberty
Males
normal external genitalia, not recognized during infancy
Treatment
Cortisol and mineralocorticoids replacement to correct electrolyte imbalances.
(Most females)surgical repair of external genitalia and psychological support
GnRH analogs and aromatase inhibitors
Bilateral adrenalectomy and circadian hydrocortisone treatment
Y-LINKED INHERITANCE
Most are related to reproduction and infertility
AUTOSOMAL DOMINANT INHERITANCE
abnormal gene in 1 of the autosomes
Characteristics
Affected parents have a 50% chance of passing on the abnormal gene to their offspring
Family members who do not have the abnormal gene are unaffected and do not pass on the disorder
Transmission is vertical (parent to child), appearing in multiple generations
Males and females are equally affected
Mutations
Familial Hypercholesterolemia (FH)
Manifestations
Elevated serum cholesterol
Premature atherosclerosis
yellow skin around the eyes
Management
Statins- inhibition of HMG CoA reductase
LDL-R gene transfer approaches
Marfan Syndrome
A connective tissue disease caused by mutation in fibrillin-1 (FBN1) gene on long arm of chromosome 15
Manifestations
Musculoskeletal deformities
tall stature, unusually long and slender limbs, scoliosis, chest wall deformities, arachnodactyly, and hyperextensibility of the joints
Cardiovascular aberrations
mitral valve prolapse, mitral regurgitation, aortic root dilatation, aortic incompetence
Ocular abnormalities
myopia and ectopia lentis
Pulmonary (spontaneous pneumothorax and apical blebs
Skin
striae atrophicae and hernias
Lumbosacral dural ectasia
Diagnosis
Revised Ghent nosology
presence of Cardiovascular
Treatment
B- blockers
Losartan
Ehlers-Danlos Syndrome
Defect in collagen structure or synthesis, resulting in abnormal production and secretion of collagen
Manifestations
Skin and blood vessel fragility, hyperextensible and transparent skin,hypermobile joints and delayed wound healing.
6 Types
Classical
Hypermobile
Vascular type
Kyphoscloliosis
Arthrochalasia
Dermatosparaxis
Management
physical therapy to strengthen muscles
Wearing of protection pads or stockings
Avoiding contact sports
Neurofibromatosis Type 1 or Von Recklinghausen Disease
Defect in tumor suppressor gene NF – 1 on chromosome 17
Manifestations
Café- au lait spots (hyperpigmented skin patches)
Lisch nodules (benign growths in the iris)
Multiple neurofibromas (benign tumors of peripheral nerves)
Optic pathway gliomas (benign tumors of the optic nerve)
Learning disabilities, short stature, seizures, hypertension
Malignancies
Management
Surgical intervention
physical evaluation every 6 months
Non-Mendelian Inheritance
TRIPLET REPEAT EXPANSION DISORDERS
Fragile X Syndrome
Characteristics
Most common form of cognitive impairment
Mutations in FMR1 gene on Xq27.3
Manifestations
Females
mental retardation, more commonly learning disabilities.
Males
narrow face with large jaw, long prominent ears and macroorchidism,
high-arched palate, velvet-like skin, hyperextensible finger joints and flat fee.
Management
Medications
manage behavioral problems
Support therapies
speech, occupational therapy and special educational services
Myotonic Dystrophy
Characteristics
Most common muscular dystrophy syndrome in adults
CTG trinucleotide repeat sequence (>45) on chromoso
Manifestations
progressive muscle atrophy, weakness, myotonia, cardiac disturbances, intellectual impairment, cataract, gonadal atrophy, insulin resistance, decreased esophageal and colonic motility, myopathic face, and infertility in women.
Management
Phenytoin and carbamazepine
GENOMIC IMPRINTING
Prader-Willi Syndrome
Characteristics
◦ Lack of expression of paternally inherited imprinted genes on chromosome 15q11-q13
Manifestations
Severe Neonatal Hypotonia and poor feeding, hyperphagia after the 1st 6 months – 1 year, development of morbid obesity, short stature, hypogonadism, learning disabilities, and behavioral and psychiatric problems.
Management
Growth hormone (GH) treatment promotes growth, reduces body fat and improves
muscle strength and lipid profiles without adverse effects
◦ Supportive: speech therapy, vocational programs for older children
Angelman Syndrome
Characteristics
Lack of expression of maternally inherited imprinted genes on chromosome 15q11-q13
Manifestations
Developmental delay and hypotonia between 6 months – 2 years of age
Severe mental retardation, absent speech, microcephaly, macrosomia, maxillary hypoplasia, prognathia, and
neurological problems with a puppet-like gait, ataxia, and epileptic seizures with specific EEG abnormalities
Management
Anti-epileptic
Physical, Occupational and Speech therapy
UNIPARENTAL DISOMY
Silver-Russell Syndrome
Manifestations
Dysmorphic features: Triangular face, prominent forehead, and clinodactyly (incurving) of the 5th digit of both hand
Some with body asymmetry (risk for abdominal tumors
Early puberty
Management
Supportive care (proper nutrition, hormone replacement, and physical therapy
Beckwith-Wiedemann Syndrome
Characteristics
Increased risk for developing kidney (Wilm’s tumor) and liver (hepatoblastoma) cancer
Need monitoring up to 8 years
Manisfestations
Large for gestational age infants,Neonatal hypoglycemia,Large tongue,Mid-face hypoplasia omphalocele, visceralomegaly and gigantism
Management
Supportive medical and surgical strategies
Screening for hypoglycemia in 1st few days up to 1st year of life
Tumor surveillance
Alpha fetoprotein (AFP) – every 3 months up to 8 years for early detection of Hepatoblastoma
MITOCHONDRIAL DISORDERS
Disorders with mtDNA Mutations
Sporadic progressive external ophthalmoplegia (PEO)
Pearson’s syndrome
Kearns-Sayre syndrome (KSS)
Mitochondrial disorders nuclear DNA (nDNA)
Paraganglioma
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)
Leigh syndrome
Friedrich ataxia
MULTIFACTORIAL INHERITANCE
Characteristics
Concordance is higher among monozygotic than dizygotic twins
Recurrence risk increases after more than 1 progeny is affected
Involve a single organ system or systems of same embryonic origin
Genetics Tests
CYTOGENETICS
◦ Study of Chromosomes – structure, morphology, organization and inheritance as applied to medical genetics
MOLECULAR GENETICS
◦ Methods
Northern Blot
Used in RNA analysis
Western Blot
Used to determine a molecular defect, and how the encoded protein of that defect produced a particular phenotype
Southern Blotting
standard used in analyzing DNA structure cleaved by restriction enzymes
FLUORESCENE IN SITU HYBRIDIZATION (FISH)
CHROMOSOMAL MICROARRAY ANALYSIS
BIOCHEMICAL TESTS
Stem Cell Therapy
EMBRYONIC STEM CELL THERAPY
ADULT STEM CELL THERAPY
Used for many years to treat leukemia through bone marrow transplants
CORD BLOOD BANKING
can be used in transplants to treat numerous disorders including leukemia, sickle cell disease, and inherited metabolic conditions
Management and Treatment of Genetic Disorders
PHYSIOLOGIC THERAPIES
used in the treatment of inborn errors of metabolism
REPLACEMENT THERAPIES
ENZYME REPLACEMENT
TRANSPLANTATION
Cell transplantation and organ transplantation
GENE THERAPY
transferring a gene into a cell, resulting in a therapeutic effect
risk
adverse immune reaction
causing mutagenesis
Chromosomal Anomalies
Sex Chromosomal Polysomes
XXY (KLINEFELTER SYNDROME)
Manisfestations
: taller than average with long arms and legs, gynecomastia, small testes and infertility
lower IQ than normal siblings
Management
Replacement with long acting testosterone, commence at 11-12 years of age
Characteristics
Common cause of primary gonadism in males
47, XYY Karyotype
Characteristics
Nondisjunction at paternal meiosis II
Manisfestations
hyperactivity, attention deficit, temper tantrums, low frustration tolerance, and learning disabilities
Structural Abnormalities
REARRANGMENT WITHIN A SINGLE CHROMOSOME
Inversions
Less common
Isochromosomes
Characteristics
2 copies of 1 arm joined through a single centromere, forming mirror images of one another, but have no copies of the other
Involvement of long arm of X chromosome (Xq) is the most common
isochromosome
Duplication
Characteristics
partial trisomy
presence of extra genetic material from the same chromosome
Ring Chromosomes
Characteristics
Deletion of both ends of a chromosome with the ends uniting to form a ring.
Deletion
Characteristics
A chromosome break and subsequent loss of genetic material
Example
Cri-du-chat syndrome (French for cry of the cat)
Deletion of the distal short arm of chromosome 5
hypotonia, microcephaly, round face, hypertelorism, bilateral epicanthic folds and mental retardation
REARRANGMENT INVOLVING MORE THAN ONE CHROMOSOME
Translocation
Characteristics
Exchange of genetic material between 2 or more non-homologous
chromosomes
Classified
Reciprocal translocation
break occurs in 2 different chromosomes with reciprocal exchange of broken segments
Robertsonian translocation
loss of short arms of 2 acrocentric chromosomes(13,14,15,21,22) and the fusion on long arms at centromere
Dicentric Chromosome
Characteristics
2 centromeres, resulting from the union of chromosomal fragments that both contain a centromere
Numerical Abnormalities
TRISOMY
◦ Trisomy 16 – most common aneuploidy in humans
Trisomy 21 or Down Syndrome
Characteristics
Most common autosomal chromosomal abnormality in humans
Most males are nearly always sterile, some females are able to produce
Manisfestations
facial and other dysmorphic features,congenital heart defects, gastrointestinal abnormalities, immune dysfunction, and hearing and visual problems,mild to moderate retardation
Management
Anticipatory care of medical complications and early developmental intervention
Trisomy 18 or Edward Syndrome
Characteristics
2nd most common chromosomal abnormality
Infants are small for gestational age
Most of those who survive have severe mental retardation
Manisfestations
Distinctive overlapping digits,Majority have congenital heart defects (particularly VSD), omphalocele, radial aplasia, and diaphragmatic hernia
Trisomy 13 or Patau Syndrome
Manisfestations
Most have holoprosencephaly, hypotelorism, cleft lip and/or palate, cardiac
defects, omphalocele, polydactyly and cutis aplasia
MONOSOMY
Characteristics
Presence of only 1 Chromosome instead of normal 2 in a diploid cell
Manisfestations
amenorrhea and short stature, Congenital heart anomalies, structural kidney abnormalities and learning disabilities may be present Ovarian dysgenesis with streaked gonads and infantile uterus – leads to absence of secondary sexual characteristics
Management
Growth hormone and estrogen replacement therapy, treatment of medical problems and psychosocial suppor
MOSAICISM
Manisfestations
neurofibromatosis, or osteogenesis imperfecta recurrence.
lethal disorders such as Trisomy 8 and milder manifestations of abnormalities such as in Trisomy 18.